Constent statement:
Written informed consent was obtained from the parents(minor patient) prior to study inclusion according to the local ethical regulations.
Abstract:Introduction: Osteogenesis Imperfecta (OI) is a rare genetic disorder characterized by increased bone fragility and recurrent fractures. OI is classified into types I-IV based on clinical features, with the majority of cases attributed to mutations in the COL1A1 and COL1A2 genes encoding type I collagen.Case Presentation: Here we present the case of a newborn with OI who exhibited widened fontanelles and short limbs. Genetic testing of the patient and parents was conducted, with validation by Sanger sequencing. At five months, comprehensive imaging studies were performed to observe skeletal development. A novel missense mutation (c.4097T>A) was identified in the COL1A1 gene of the patient; however, neither the mother nor father carried this mutation. At five months, the child exhibited lower height and weight than normal infants, along with shortened limbs. Radiographic examination revealed slender limb bones and reduced bone density. Based on the clinical presentation and genetic testing, a diagnosis of type IV Osteogenesis Imperfecta (OI) was established. Conclusion: Overall, in this case we present a new mutation site (c.4097T>A; p.Ile1366Asn) in COL1A1 in a patient with OI. This mutation suggests a potential link to Type IV OI in the Chinese population, and this case contributes to the diversity of COL1A1 pathogenic mutations.Keywords Type IV OI; Type I collagen; COL1A1 gene; novel mutation.
Introduction
Osteogenesis Imperfecta (OI) is a hereditary disorder characterized by fragile and deformed bones, recurrent fractures, blue sclera, incomplete tooth development, short stature, and progressive hearing loss. More than 90% of OI cases result from mutations in the genes COL1A1 and COL1A2, which encode Type I collagen, and the inheritance pattern is typically autosomal dominant. The prevalence of OI is extremely low, estimated to be approximately 1 in 15,000-20,000 individuals[1]. In Europe and the United States, the reported birth prevalence ranges from 3-7/100,000[2-3], whereas in Finland, approximately 0.5/10,000 people are affected[4]. OI is categorized into four types based on the severity of clinical manifestations, as follows: Type I (mild), Type II (lethal), Type III (severe deformities), and Type IV (moderate deformities), with Type I being the most common[5-6]. Statistical data on the prevalence of OI in the Chinese population are currently lacking. However, according to Li et al.[7], among 668 patients with OI from 378 Chinese families, Type I accounted for 39%, and Type IV accounted for 35% of cases. Here we present the case of a newborn diagnosed with OI ultimately confirmed as Type IV, and detail the diagnostic and therapeutic processes based on genetic testing and clinical observations.
Case History and Examination
The patient was a female infant with the chief complaint of premature rupture of the membranes at 26 h, born after 37 min of labor, with a birth weight of 2500 g. Physical examination revealed a head circumference of 32 cm, noticeable widening of the anterior fontanelle, and a sagittal suture with a maximum width of 4.5 cm. Other findings included white sclera, multiple missing teeth in both the upper and lower jaws, outward expansion of the bilateral rib cage, no apparent spinal deformities, short limbs, and wrinkled skin on the palms and soles. Based on the patient’s clinical presentation of the newborn, OI was suspected. Targeted high-throughput sequencing was employed to conduct genetic testing on the patient and her parents, identifying a heterozygous, potentially pathogenic variant of the COL1A1 gene, specifically c.4097T>A (p.Ile1366Asn), which correlated strongly with the patient’s clinical phenotype (Table 1). The mutation site was verified by Sanger sequencing, while First-generation Sanger sequencing indicated that the parents did not carry the COL1A1 c.4097T>A mutation (Figure 1) . Upon a follow-up visit at 5 months of age, the patient exhibited slower growth than normal infants. Her weight was 3000 g, height was 60 cm, and the sagittal suture of the skull was approximately 4cm wide with a grayish-white sclera. The spine showed no signs of lateral deformity and the limbs were relatively short. Radiographic examination revealed thinning of the bilateral humerus, radius, femur, and tibia-fibula bones; slight curvature of the radius and ulna; and underdeveloped and shallow hips on both sides (Figure2) .
Methods
Differential diagnosis OI needs to be differentiated from Osteopetrosis and Osteoporosis[8-9]. Osteopetrosis: Osteopetrosis is a rare metabolic bone disease characterized by widespread calcification of the entire skeletal system and thickening of bone cortices. Osteoporosis: Osteoporosis is a common metabolic bone disease characterized by decreased bone mass and microstructural damage to bone tissue, leading to bone fragility and susceptibility to fractures. X-rays of osteoporosis patients may show reduced bone mass and blurred trabeculae, which resemble the X-ray features of osteogenesis imperfecta. However, osteoporosis patients typically have a negative family history.